This program-project grant will continue the only study of the interrelationships of multiple etiologic factors that include the influence of breast fluid biochemistry and epidemiologic characteristics on breast cytology and histologically-defined breast disease. The program will conduct multidisciplinary epidemiologic and laboratory studies of women with breast cancer, biopsied benign breast disease, and of women with no histologic evidence of breast disease but with varying risk of breast cancer. Laboratory studies will include measurement of cholesterol, cholesterol epoxides, and hormones in nipple aspirates of breast fluid; cholesterol and hormones in blood; cytology of breast fluid cells; and pathology review of breast tissue. There are five projects. Project 1 will model the interrelationships of these factors and will longitudinally assess the influence of reproductive factors on breast fluid constituents and cytology. Project 2 will study Chinese women to assess the relationship between breast fluid secretion, diet and breast cancer risk in a group of women whose risk is rapidly increasing; this study may identify dietary factors that would be useful in prevention of breast cancer in Chinese and non-Chinese women. Project 3 is an 8- to 18-year follow-up study of 5206 women from this program's previous breast fluid studies and will assess the risk of breast cancer among women with atypical cytologic findings. Project 4 will use image and flow cytometry to determine objective and reproducible parameters for classification of premalignant breast disease. Project 5 will examine regulation of estrogen synthesis in adipose cells from the breast and other body sites. Data from these studies will lead to better understanding of the natural history of breast diseases with the goals of improving the diagnosis of premalignant breast disease and breast cancer risk counseling, and aiding rational development of preventive strategies.